Hepatitis A and E vaccines. The HVS in collaboration with GlaxoSmithKline (GSK), Rixensart, Belgium, has developed several candidate live attenuated HAV vaccines. One such candidate was modified to become the currently licensed GSK inactivated HAV vaccine. In addition, the HVS has developed a candidate recombinant hepatitis E vaccine that is highly promising and that has recently completed clinical trials. In studies to further characterize this candidate hepatitis E vaccine, we have performed extensive pre-clinical trials to determine the potency of the vaccine, the duration of protection, the optimum regimen for administration, its protective efficacy against homologous versus heterologous virus strains, its ability to prevent infection as well as hepatitis and the minimum antibody titer that was effective in preventing infection and hepatitis, respectively. In the clinical trial, the vaccine was 96% efficacious in preventing hepatitis E following three doses of vaccine and 87% efficacious following two doses. The vaccine had no detectable side effects. These results are outstanding for a vaccine. GSK is currently determining its plans for future manufacture and distribution of the vaccine.[unreadable] Hepatitis B and C vaccines. The HVS has studied the technology of DNA vaccines with a model system based upon hepatitis B virus (HBV) vaccine, a vaccine with which the HVS has had extensive experience. We have tested the efficacy of an immunostimulant (CpG) as an adjuvant for DNA vaccines, as well as for protein vaccines. Protein vaccines were found to be superior to DNA vaccines when compared in chimpanzees, a surrogate of man. CpG provided a greater but short-lived antibody response when compared to alum adjuvant. In addition, the utility of DNA vaccines for the control of hepatitis C virus (HCV) has been explored. A DNA vaccine based on the E2 envelope protein of HCV proved to be highly immunogenic in mice and rhesus monkeys and moderately immunogenic in chimpanzees, but the chimpanzees were not fully protected when they were challenged with live HCV. A similar approach has been utilized in the study of a DNA vaccine based on the E1 envelope protein of HCV: various constructs of the E1 gene were prepared as DNA vaccines (expression vector plasmids) and as vectored vaccines (recombinant vaccinia) and tested in mice. The mice had excellent immune responses to the DNA vaccine as well as to the vaccinia boost. In other studies, recombinant HCV E1 envelope glycoprotein has been tested in chimpanzees as an immunoprophylactic vaccine. This vaccine, developed by Innogenetics and tested by HVS as part of a CRADA with the company, was administered to 9 chimpanzees, which were then challenged with virulent HCV provided by the HVS. As described in another annual report, we have identified in vitro correlates of protection that will be instrumental in identifying ineffective vaccines before testing in chimpanzees.